It is the intent of all sustained-release pharmaceutical preparations to provide a longer period of pharmacologic effect after the administration of a drug than is ordinarily experienced after the administration of immediate release preparations of the same drug. Such longer periods of efficacy can provide many inherent therapeutic benefits that are not achieved with corresponding immediate release preparations. The benefits of prolonged treatment of hypertension (high blood pressure) afforded by sustained release oral preparations have become universally recognized and oral sustained-release preparations are commercially available.
Another approach to sustained delivery of a therapeutically active agent is transdermal delivery systems, such as transdermal patches. Generally, transdermal patches contain a therapeutically active agent, a reservoir or matrix containing the active ingredient(s) and an adhesive which allows the transdermal device to adhere to the skin, allowing for the passage of the active agent from the device through the skin of the patient. Once the active agent has penetrated the skin layer, the drug is absorbed into the blood stream where it can exert a desired pharmacotherapeutic effect.
Transdermal delivery of antihypertensives, such as felodipine, have been contemplated. For example, U.S. Pat. No. 5,834,496 issued Nov. 10, 1998 to Young, hereby incorporated by reference, relates to methods and compositions utilizing the optical pure (—S) isomer of felodipine for treating conditions such as hypertension, angina, cerebral ischemia, cerebral disorders, arrhythmias, cardiac hypertrophy, coronary vasospasm, myocardial infarction, renal impairment and acute renal failure.
Felodipine, commercially available as Plendil® in the U.S. from AstraZeneca Pharmaceuticals LP (Wilmington, Del. 15437, U.S.A.), is a calcium antagonist (calcium channel blocker). Specifically, felopine is a dihydropyridine derivative with the chemical name, 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate, and it is used in the treatment of hypertension. It is a racemic mixture, and it is in the form of a slightly yellowish powder that is not soluble in water but freely soluble in dichloromethane and ethanol. Felodipine causes a decrease in the intracellular concentration of calcium ions, which leads to a reduction in blood pressure. The recommended starting oral dosage of felodipine is 5 mg once daily, and depending on the response of the patient can be increased up to 10 mg daily or decreased to 2.5 mg daily. In elderly patients or patients with liver or renal problems, the initial oral dosage felodopine should be 2.5 mg daily with the dosage being adjustable as set forth above.
High blood pressure or hypertension occurs when the blood exerts excessive force upon the walls of the arteries. Blood pressure is measured as two numbers; systolic (pressure of the blood in the arteries when the heart beats) and diastolic (pressure when the heart is at rest between heartbeats). A normal blood pressure is consider to be around 120 (systolic)/80 (diastolic) mm Hg, whereas a reading of about 140 (systolic)/90 (diastolic) mm Hg or higher is considered to be high blood pressure. High blood pressure causes the heart to work extra hard, which in turn eventually leads to an enlarged heart, putting the individual at increased risk of having a heart attack or stroke. Some possible causes of high blood pressure include thinning of the arteries, increased heart rate, increased volume of blood, excitement, and nervousness.
Symptoms of hypertension are improved by treatment with a group of antihypertensives known as calcium channel antagonists (calcium channel blockers). Calcium channel antagonists such as felodipine (The Merck Index, 11th Edition, Merck & Co., Inc., Rahway, N.J. U.S.A. 1989, hereby incorporated by reference) inhibit the influx of extracellular calcium across the membranes of the myocardial and vascular smooth muscle cells, causing the blood vessels to relax, and thereby reducing blood pressure. (Goodman and Gillmans, The Pharmacological Basis of Therapeutics, 9th Edition, hereby incorporated by reference). Felodipine has a greater selectively for vascular smooth muscle than for cardiac muscle.
Following oral administration, felodipine is rapidly absorbed and undergoes extensive first pass metabolism, resulting in a bioavailibility of approximately 20 percent. Pharmacokinetic studies have revealed that the onset of antihypertensive activity occurs within 2–5 hours following administration of felodipine. Mean peak concentrations are reached in 2.5–5 hours after administration. The mean elimination half-life is roughly 11 to 16 hours. Metabolism of felodopine results in its excretion in the urine (70%) and the feces (10%). Felodipine is 99% plasma-protein bound.
The most common adverse side effects of felopidine are peripheral edema and headaches. Other side effects include chest infection, dizziness, palpitations, diarrhea, constipation, flushing, rash, fatigue, and gingival enlargement (Physicians' Desk Reference, 53rd Edition, 1999, hereby incorporated by reference).
Despite advances in the art, there remains a need for methods of treating patients with hypertension with an agent that provides effective levels of felodipine for prolonged periods of time while eliminating or minimizing the symptoms of hypertension, and the above mentioned side effects, thus providing a safe and effective method of management of this condition.